Oxygen-substituted phenylacetic acids are known compounds which have been used in the synthesis of a wide variety of natural products, including flavonoids and alkaloids. Of these, 3-hydroxy-4-methoxyphenyl acetic acid is one of the basic raw materials for the synthesis of natural and unnatural opium derivatives, including antagonists and agonist-antagonists. More particularly, the present inventor has used 3-hydroxy-4-methoxyphenylacetic acid in a concise synthesis of the opiate precursor dihydrothebainone, J. Oro. Chem. 45: 3135, 1980. Prior methods have one or more of the disadvantages of requiring high pressure, high reaction temperature, undue use of hazardous solvents such as ether and producing product in low yield and impure state.
Weller et al, in J.Org. Chem. 49:2061-2063 (1984) disclose a method for synthesizing oxygenated phenylacetic acids by brominating 4-methoxyphenylacetic acid and then displacing the bromine by hydroxide in a copper-catalyzed reaction under pressure.
Reeve, in U.S. Pat. No. 3,086,990, discloses a process for producing m-chloro- and m- and p-fluoroalpha-methoxyphenylacetic acid from the corresponding halogenated benzaldehydes in bromoform with potassium hydroxide in methanol.
Eckert et al, in U.S. Pat. No. 2,228,920, disclose a process for preparing 5-hydroxy-trimellitic acid by treating a 5-halogen pseudocumene with an oxidizing agent and heating the obtained 5-halogentrimellitic acid with an alkali or an agent having an alkaline reaction.
Dubin et al, in U.S. Pat. No. 1,529,946, disclose a process for preparing fatty acids of the acetic acid series from their higher homologs by converting the acid to the corresponding halogen acid, treating the halogen acid with an alkaline reagent capable of replacing the halogen by a hydroxyl group, oxidizing the hydrolyzed product of the alkaline treatment, and recovering the resulting acid. Each procedure produces an acid containing one less carbon atom than the acid so treated.
Whitmore et al, in U.S. Pat. No. 2,240,275, disclose a method for preparing highly branched brominated organic acids by treating the starting acid with liquid bromine in the presence of a catalyst so that the bromine becomes attached to the carbon atom in the alpha position with respect to the carboxy radical.